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Dec 21, 2011

Research Teams Independently Identify New HIV-1 Target

  • Three papers published simultaneously in Nature have provided new insights into the network of interactions between HIV-1 and human proteins, and identified potential new targets for therapeutic intervention. In one of the papers, a University of California, San Francisco (UCSF)-led team describes the use of an affinity tagging/purification mass spectrometry (AP-MS) approach to systematically determine the physical interactions of all 18 HIV-1 proteins and polyproteins with host proteins in two different human cell lines (HEK293 and Jurkat). In a second paper, the team looks further at the previously unreported finding that the human transcription cofactor CBF-β (core binding factor β) is required by the HIV accessory factor, Vif, to enable degradation of the naturally protective DNA deaminase APOBEC3G, and maintain viral infectivity.

    This Vif-CBF-β interaction and its potential as a target for HIV-1 therapy is separately supported by an independent research team led at the First Hospital of Jilin University, Institute of Virology and AIDS Research in China, and the Johns Hopkins Bloomberg School of Public Health.

    In their primary paper, titled “Global landscape of HIV–human protein complexes,” the UCSF researchers, led by Nevan J. Krogan, Ph.D., identified 497 HIV–human protein interactions involving 435 separate human proteins. Forty percent of these interactions were identified in both the HEK293 and Jurkat cell lines, and many of the host proteins hijacked by HIV were highly conserved across primates.

    When the team analyzed the functional categories of host proteins associated with each HIV protein, they found an enrichment of host factors involved in transcription physically linked to the HIV transcription factor Tat. There was in addition an enrichment of host proteins thought to be involved in the regulation of ubiquitination associating with Vpu, Vpr, and Vif, which are HIV accessory factors that hijack ubiquitin ligases. One notable finding was that HIV protease cleaves eIF3d, a subunit of eukaryotic translation initiation factor 3, and one of 11 host proteins identified that acts to inhibit HIV replication.

    The UCSF’s analyses also identified a physical interaction between the HIV accessory protein, Vif, and the transcription cofactor CBF-β, as part of its hijacking of a ubiquitin ligase complex that targets APOBEC3G for degradation. Additional RNA knockdown and genetic complementation studies reported in the team’s second paper indicate that CBF-β is required for Vif-mediated degradation of APOBEC3G, and for preserving HIV-1 infectivity. In this paper, titled “Vif hijacks CBF-b to degrade APOBEC3G and promote HIV-1 infection,” the UCSF team concludes that “methods of disrupting the CBF-β–Vif interaction might enable HIV-1 restriction and provide a supplement to current antiviral therapies that primarily target viral proteins.”

    This latter work is supported by the Jilin University and Johns Hopkins team, led by Xiao-Fang Yu, Ph.D. Dr. Yu et al report on independent studies demonstrating that CBF-b is a key regulator of HIV-1 Vif function. Their work, including CBF-β knockdown studies, showed that CBF-β is critical for Vif-induced endogenous APOBEC3G degradation and HIV-1 replication in H9 CD4+ T cells. While the results indicated that CGF-β isn’t required for the interaction between Vif and APOBEC3G, it was essential for assembly of the Vif ubiquitin-ligase complex. “Considering the importance of the interaction between Vif and CBF-b, disrupting this interaction represents an attractive pharmacological intervention against HIV-1,” they conclude. The investigators report their findings in a paper titled “T-cell differentiation factor CBF-b regulates HIV-1 Vif-mediated evasion of host restriction.”

     


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